The NYU Lung Cancer Biomarker Center CVC has recruited 1143 high-risk smokers (SCREENING COHORT) for the early detection of lung cancer. We have evaluated 1047 study subjects in our R/0 LUNG CANCER COHORT in collaboration with Harvey Pass, MD and the Division of Thoracic Surgery. Questionnaires, blood (100ml), spirometry, sputum, and CT-scans are obtained. 52% of the SCREENING COHORT had non-calcified nodules (NCN) with 3771 CT-Scans obtained to assess growth rates. 22 thoracic neoplasms were diagnosed with 18 lung adenocarcinomas. Biomarker collaborations with D, Sidransky Johns Hopkins) identified a panel of genes with promoter hypermethylations in plasma from lung cancer patients. Consistent with this finding, we noted increased plasma S- adenosylmethionine, a key intermediate in the methylation pathway, in lung cancer patients compared to high-risk smokers with NCN. Using set aside funds, we showed a 29-gene expression pattern in PBMC that separated lung cancer from high-risk controls with L, Showe (Wistar, UPenn), M-s Tang and colleagues demonstrated DNA adducts occurred at hot spot mutation sites in p53 and K-ras, and that poor repair contributed to adduct persistence. Exhaled breath predicted lung cancer with high AUC using combinations of alkanes measured in GC/MS. Our research plan is to expand our CVC with 300 new high-risk smokers, 1000 follow-up NCNs, and > 250 lung cancers. We will evaluate NCN by CT- scans for early detection. We will determine risk for lung cancer among high-risk smokers by measuring blood acrolein DNA adducts and PBMC DNA repair capacity. We will develop a phase 3 validation case control study of 200 lung cancer cases and 200 matched controls and a phase 4 validation cohorts study of 600 high-risk smokers with >40 incident lung cancers. We will evaluate serum for tumor-associated antigens, auto-antibodies, gene expression patterns in PBMC and pathway control by microRNAs. Importantly, we will cross validate biomarker panels in the same prospective high risk smoker cohorts.